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1.  Regionally Selective Atrophy after Traumatic Axonal Injury 
Archives of neurology  2010;67(11):1336-1344.
To determine the spatial distribution of cortical and subcortical volume loss in patients with diffuse traumatic axonal injury and to assess the relationship between regional atrophy and functional outcome.
Prospective imaging study. Longitudinal changes in global and regional brain volumes were assessed using high-resolution magnetic resonance imaging (MRI)-based morphometric analysis.
Inpatient traumatic brain injury unit
Patients or Other Participants
Twenty-five patients with diffuse traumatic axonal injury and 22 age- and sex-matched controls.
Main Outcome Measure
Changes in global and regional brain volumes between initial and follow-up MRI were used to assess the spatial distribution of post-traumatic volume loss. The Glasgow Outcome Scale – Extended was the primary measure of functional outcome.
Patients underwent substantial global atrophy with mean brain parenchymal volume loss of 4.5% (95% Confidence Interval: 2.7 – 6.3%). Decreases in volume (at a false discovery rate of 0.05) were seen in several brain regions including the amygdala, hippocampus, thalamus, corpus callosum, putamen, precuneus, postcentral gyrus, paracentral lobule, and parietal and frontal cortices, while other regions such as the caudate and inferior temporal cortex were relatively resistant to atrophy. Loss of whole brain parenchymal volume was predictive of long-term disability, as was atrophy of particular brain regions including the inferior parietal cortex, pars orbitalis, pericalcarine cortex, and supramarginal gyrus.
Traumatic axonal injury leads to substantial post-traumatic atrophy that is regionally selective rather than diffuse, and volume loss in certain regions may have prognostic value for functional recovery.
PMCID: PMC3465162  PMID: 20625067
2.  Loss of a 20S Proteasome Activator in Saccharomyces cerevisiae Downregulates Genes Important for Genomic Integrity, Increases DNA Damage, and Selectively Sensitizes Cells to Agents With Diverse Mechanisms of Action 
G3: Genes|Genomes|Genetics  2012;2(8):943-959.
Cytoprotective functions of a 20S proteasome activator were investigated. Saccharomyces cerevisiae Blm10 and human 20S proteasome activator 200 (PA200) are homologs. Comparative genome-wide analyses of untreated diploid cells lacking Blm10 and growing at steady state at defined growth rates revealed downregulation of numerous genes required for accurate chromosome structure, assembly and repair, and upregulation of a specific subset of genes encoding protein-folding chaperones. Blm10 loss or truncation of the Ubp3/Blm3 deubiquitinating enzyme caused massive chromosomal damage and cell death in homozygous diploids after phleomycin treatments, indicating that Blm10 and Ubp3/Blm3 function to stabilize the genome and protect against cell death. Diploids lacking Blm10 also were sensitized to doxorubicin, hydroxyurea, 5-fluorouracil, rapamycin, hydrogen peroxide, methyl methanesulfonate, and calcofluor. Fluorescently tagged Blm10 localized in nuclei, with enhanced fluorescence after DNA replication. After DNA damage that caused a classic G2/M arrest, fluorescence remained diffuse, with evidence of nuclear fragmentation in some cells. Protective functions of Blm10 did not require the carboxyl-terminal region that makes close contact with 20S proteasomes, indicating that protection does not require this contact or the truncated Blm10 can interact with the proteasome apart from this region. Without its carboxyl-terminus, Blm10(−339aa) localized to nuclei in untreated, nonproliferating (G0) cells, but not during G1 S, G2, and M. The results indicate Blm10 functions in protective mechanisms that include the machinery that assures proper assembly of chromosomes. These essential guardian functions have implications for ubiquitin-independent targeting in anticancer therapy. Targeting Blm10/PA200 together with one or more of the upregulated chaperones or a conventional treatment could be efficacious.
PMCID: PMC3411250  PMID: 22908043
20S proteasome activator; BLM10/PA200; UBP3/BLM3; DNA damage; molecular chaperones
3.  Plasma 24S-hydroxycholesterol and other oxysterols in acute closed head injury 
Brain Injury  2008;22(7-8):611-615.
Primary objective
To determine if plasma levels of 24S-hydroxycholesterol, the primary catabolite of brain cholesterol, provide a measure of axonal damage in acute brain trauma.
Research design
Determination of plasma 24S-hydroxycholesterol in a series of persons admitted to an intensive care unit for treatment of closed head injury.
Methods and procedures
Levels of 24-S-hydroxycholesterol, 27-hydroxycholesterol, lathosterol and total cholesterol were measured in peripheral blood from 38 persons from 14–55 years of age treated by craniotomy and ventriculostomy for intractable intracerebral hypertension. Severity of brain injury was estimated by the Glasgow Coma Scale (range = 3–13, median = 6 points) and overall injury by the Injury Severity Scale (range = 10–48, median = 29). All subjects were intubated and anaesthetized with intravenous propofol. Plasma sterol levels were compared with those of age-matched control subjects.
Outcomes and results
There was no significant increase in plasma 24-S-hydroxycholesterol in subjects with head injury, but measures of peripheral cholesterol synthesis were markedly reduced as compared with values for age-matched normal control subjects.
Plasma 24S-hydroxycholesterol levels do not change with severe closed head injury.
PMCID: PMC3399688  PMID: 18568715
Closed head injury; 24-S-hydroxycholesterol; oxysterols
5.  Assessing Spatial Relationships between Axonal Integrity, Regional Brain Volumes, and Neuropsychological Outcomes after Traumatic Axonal Injury 
Journal of Neurotrauma  2010;27(12):2121-2130.
Diffuse traumatic axonal injury (TAI) is a type of traumatic brain injury (TBI) characterized predominantly by white matter damage. While TAI is associated with cerebral atrophy, the relationship between gray matter volumes and TAI of afferent or efferent axonal pathways remains unknown. Moreover, it is unclear if deficits in cognition are associated with post-traumatic brain volumes in particular regions. The goal of this study was to determine the relationship between markers of TAI and volumes of cortical and subcortical structures, while also assessing the relationship between cognitive outcomes and regional brain volumes. High-resolution magnetic resonance imaging scans were performed in 24 patients with TAI within 1 week of injury and were repeated 8 months later. Diffusion tensor imaging (DTI) tractography was used to reconstruct prominent white matter tracts and calculate their fractional anisotropy (FA) and mean diffusivity (MD) values. Regional brain volumes were computed using semi-automated morphometric analysis. Pearson's correlation coefficients were used to assess associations between brain volumes, white matter integrity (i.e., FA and MD), and neuropsychological outcomes. Post-traumatic volumes of many gray matter structures were associated with chronic damage to related white matter tracts, and less strongly associated with measures of white matter integrity in the acute scans. For example, left and right hippocampal volumes correlated with FA in the fornix body (r = 0.600, p = 0.001; r = 0.714, p < 0.001, respectively). In addition, regional brain volumes were associated with deficits in corresponding neuropsychological domains. Our results suggest that TAI may be a primary mechanism of post-traumatic atrophy, and provide support for regional morphometry as a biomarker for cognitive outcome after injury.
PMCID: PMC2996819  PMID: 20874032
atrophy; diffuse axonal injury; diffusion tensor imaging; traumatic brain injury; volumetric magnetic resonance imaging
6.  Decreased C-Reactive Protein Levels in Alzheimer Disease 
C-reactive protein (CRP) is an acute-phase reactant that has been found to be associated with Alzheimer disease (AD) in histo-pathological and longitudinal studies; however, little data exist regarding serum CRP levels in patients with established AD. The current study evaluated CRP levels in 192 patients diagnosed with probable AD (mean age = 75.8 ± 8.2 years; 50% female) as compared to 174 nondemented controls (mean age = 70.6 ± 8.2 years; 63% female). Mean CRP levels were found to be significantly decreased in AD (2.9 µg/mL) versus controls (4.9 µg/mL; P = .003). In adjusted models, elevated CRP significantly predicted poorer (elevated) Clinical Dementia Rating Scale sum of boxes (CDR SB) scores in patients with AD. In controls, CRP was negatively associated with Mini-Mental State Examination (MMSE) scores and positively associated with CDR SB scores. These findings, together with previously published results, are consistent with the hypothesis that midlife elevations in CRP are associated with increased risk of AD development though elevated CRP levels are not useful for prediction in the immediate prodrome years before AD becomes clinically manifest. However, for a subgroup of patients with AD, elevated CRP continues to predict increased dementia severity suggestive of a possible proinflammatory endophenotype in AD.
PMCID: PMC3204581  PMID: 19933496
Alzheimer disease; C-reactive protein; inflammation; treatment; primary prevention
7.  Prediction of Failure in Vancomycin-Treated Methicillin-Resistant Staphylococcus aureus Bloodstream Infection: a Clinically Useful Risk Stratification Tool▿† 
Antimicrobial Agents and Chemotherapy  2011;55(10):4581-4588.
Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of bloodstream infection (BSI) and is often associated with invasive infections and high rates of mortality. Vancomycin has remained the mainstay of therapy for serious Gram-positive infections, particularly MRSA BSI; however, therapeutic failures with vancomycin have been increasingly reported. We conducted a comprehensive evaluation of the factors (patient, strain, infection, and treatment) involved in the etiology and management of MRSA BSI to create a risk stratification tool for clinicians. This study included consecutive patients with MRSA BSI treated with vancomycin over 2 years in an inner-city hospital in Detroit, MI. Classification and regression tree analysis (CART) was used to develop a risk prediction model that characterized vancomycin-treated patients at high risk of clinical failure. Of all factors, the Acute Physiology and Chronic Health Evaluation II (APACHE-II) score, with a cutoff point of 14, was found to be the strongest predictor of failure and was used to split the population into two groups. Forty-seven percent of the population had an APACHE-II score < 14, a value that was associated with low rates of clinical failure (11%) and mortality (4%). Fifty-four percent of the population had an APACHE-II score ≥ 14, which was associated with high rates of clinical failure (35%) and mortality (23%). The risk stratification model identified the interplay of three other predictors of failure, including the vancomycin MIC as determined by Vitek 2 analysis, the risk level of the source of BSI, and the USA300 strain type. This model can be a useful tool for clinicians to predict the likelihood of success or failure in vancomycin-treated patients with MRSA bloodstream infection.
PMCID: PMC3186992  PMID: 21825294
8.  Deficits in Functional Connectivity of Hippocampal and Frontal Lobe Circuits after Traumatic Axonal Injury 
Archives of neurology  2011;68(1):74-84.
To examine the functional connectivity (fc) of hippocampal and selected frontal lobe circuits among patients with traumatic axonal injury (TAI).
Echo-planar and high-resolution T1-weighted images were acquired using 3 Tesla scanners. Regions of interest (ROI) were drawn bilaterally for the hippocampus, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC), and were used to extract time series data. BOLD data from each ROI were used as reference functions for correlating with all other brain voxels. Interhermispheric fc was assessed for each participant by correlating homologous regions using a Pearson correlation coefficient. Patient functional and neurocognitive outcomes were assessed approximately 6 months post-injury.
Patients were recruited within days of their injury while in an inpatient traumatic brain injury unit. Imaging and neurocognitive assessments were conducted in an outpatient research facility.
25 consecutive patients with brain injuries consistent with TAI and acute subcortical white matter abnormalities were studied. Sixteen healthy volunteers of similar age and gender were recruited.
Main Outcome Measures
Interhemispheric fc for each ROI was compared between patients and controls. Spatial patterns of fc were examined for each of the three ROIs. Connectivity measures were examined for associations with functional and neurocognitive outcomes.
Patients showed significantly lower interhemispheric fc for the hippocampus and ACC. Healthy controls demonstrate stronger and more focused fc for hippocampi and ACC, and a more focused recruitment of the default mode network for the DLPFC ROI. The interhemispheric fc for the hippocampus was correlated to delayed recall of verbal information.
Our findings suggest that traumatic axonal injury impacts interhemispheric neural activity, as patients with TAI show disrupted interhemipsheric fc. These results suggest more careful investigation of interhemisheric connectivity is warranted, as it demonstrated a modest association with outcome in chronic TBI.
PMCID: PMC3100186  PMID: 21220676
9.  Diffusion Tensor Imaging Biomarkers for Traumatic Axonal Injury: Analysis of Three Analytic Methods 
Traumatic axonal injury (TAI) is a common mechanism of traumatic brain injury not readily identified using conventional neuroimaging modalities. Novel imaging modalities such as diffusion tensor imaging (DTI) can detect microstructural compromise in white matter (WM) in various clinical populations including TAI. DTI-derived data can be analyzed using global methods (i.e., WM histogram or voxel based approaches) or a regional approach (i.e., tractography). While each of these methods produce qualitatively comparable results, it is not clear which is most useful in clinical research and ultimately in clinical practice. This study compared three methods of analyzing DTI-derived data with regard to detection of WM injury and their association with clinical outcomes. Thirty patients with TAI and 19 demographically similar normal controls were scanned using a 3T magnet. Patients were scanned approximately eight months post-injury, and underwent an outcomes assessment at that time. Histogram analysis of FA and MD showed global WM integrity differences between patients and controls. Voxel-based and tractography analyses showed significant decreases in FA within centroaxial structures involved in TAI. All three techniques were associated with functional and cognitive outcomes. DTI measures of microstructural integrity appear robust, as the three analysis techniques studied showed adequate utility for detecting WM injury.
PMCID: PMC3097093  PMID: 21070694
DTI; DAI; Traumatic Brain Injury; memory; Tractography; cognitive outcomes
10.  Evaluation of Risk Factors for Coinfection or Cocolonization with Vancomycin-Resistant Enterococcus and Methicillin-Resistant Staphylococcus aureus▿  
Journal of Clinical Microbiology  2009;48(2):628-630.
We retrospectively evaluated 410 patients with coinfection or cocolonization due to vancomycin-resistant (VR) enterococcus (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). The prevalence rate was 19.8%. Risk factors included isolation of VR Enterococcus faecalis and use of linezolid or clindamycin. Inc18-like vanA plasmids were found in 7% of VR E. faecalis isolates and none of the VR E. faecium isolates.
PMCID: PMC2815608  PMID: 20007403
12.  Cerebral Atrophy after Traumatic White Matter Injury: Correlation with Acute Neuroimaging and Outcome 
Journal of Neurotrauma  2008;25(12):1433-1440.
Traumatic brain injury (TBI) is a pathologically heterogeneous disease, including injury to both neuronal cell bodies and axonal processes. Global atrophy of both gray and white matter is common after TBI. This study was designed to determine the relationship between neuroimaging markers of acute diffuse axonal injury (DAI) and cerebral atrophy months later. We performed high-resolution magnetic resonance imaging (MRI) at 3 Tesla (T) in 20 patients who suffered non-penetrating TBI, during the acute (within 1 month after the injury) and chronic stage (at least 6 months after the injury). Volume of abnormal fluid-attenuated inversion-recovery (FLAIR) signal seen in white matter in both acute and follow-up scans was quantified. White and gray matter volumes were also quantified. Functional outcome was measured using the Functional Status Examination (FSE) at the time of the chronic scan. Change in brain volumes, including whole brain volume (WBV), white matter volume (WMV), and gray matter volume (GMV), correlates significantly with acute DAI volume (r = −0.69, −0.59, −0.58, respectively; p < 0.01 for all). Volume of acute FLAIR hyperintensities correlates with volume of decreased FLAIR signal in the follow-up scans (r = −0.86, p < 0.001). FSE performance correlates with acute hyperintensity volume and chronic cerebral atrophy (r = 0.53, p = 0.02; r = −0.45, p = 0.03, respectively). Acute axonal lesions measured by FLAIR imaging are strongly predictive of post-traumatic cerebral atrophy. Our findings suggest that axonal pathology measured as white matter lesions following TBI can be identified using MRI, and may be a useful measure for DAI-directed therapies.
PMCID: PMC2858299  PMID: 19072588
MR imaging; post-traumatic atrophy; TBI
13.  Trends in US Hospital Admissions for Skin and Soft Tissue Infections 
Emerging Infectious Diseases  2009;15(9):1516-1518.
Using data from the 2000–2004 US Healthcare Cost and Utilization Project National Inpatient Sample, we found that total hospital admissions for skin and soft tissue infections increased by 29% during 2000–2004; admissions for pneumonia were largely unchanged. These results are consistent with recent reported increases in community-associated methicillin-resistant Staphylococcus aureus infections.
PMCID: PMC2819854  PMID: 19788830
Skin infections; soft tissue infections; hospital admissions; staphylococci; methicillin-resistant Staphylococcus aureus; MRSA; bacteria; antimicrobial resistance; United States; dispatch
14.  Molecular Epidemiology of Methicillin-Resistant Staphylococcus aureus Bloodstream Isolates in Urban Detroit▿  
Journal of Clinical Microbiology  2008;46(7):2345-2352.
To gain a better understanding of epidemiology of resistance in Staphylococcus aureus, we describe the molecular epidemiology of methicillin-resistant Staphylococcus aureus bloodstream isolates in urban Detroit. Bloodstream isolates from July 2005 to February 2007 were characterized. Two hundred ten bloodstream isolates from 201 patients were evaluated. Patient characteristics were as follows: median age, 54 years; 56% male; and 71% African-American. Seventy-six percent of infections were health care associated, with 55% being community-onset infections and 21% hospital acquired, and 24% were community associated. The most common sources were skin/wound (25%), central venous catheters (24%), unknown source (20%), and endocarditis (9%). Ninety percent and 5% of isolates had a MIC of vancomycin of ≤1.0 mg/liter, using automated dilution testing and E-test, respectively. Six percent of isolates showed heteroresistance to vancomycin, all occurring with isolates having a vancomycin E-test MIC of ≥1.5 mg/liter. Results of pulsed-field gel electrophoresis showed 17 strain types. The predominant strains were USA100 (104 isolates) and USA300 (74 isolates). Forty-nine percent of the isolates had staphylococcal cassette chromosome mec II, and 56% had agr II. All USA300 isolates were positive for the Panton-Valentine leukocidin toxin genes and agr I. Forty-seven percent of USA300 bloodstream infections were health care associated (35% community onset and 12% hospital onset). USA300 strains were more common in injection drug users with skin/wound as the predominant source of infection. Thirty percent of the USA100 strains were closely related to vancomycin-resistant Staphylococcus aureus isolates. The results of this study show that vancomycin MICs using automated dilution testing with Vitek-2 and E-test were highly discordant. Most methicillin-resistant S. aureus strains causing bacteremia are health care associated, commonly have MICs of vancomycin that are high within the susceptible range are not detected by routine automated dilution testing, and have significant diversity of molecular characteristics. USA100 strains that are closely related to vancomycin-resistant S. aureus (VRSA) isolates and USA300 strains are common as causes of both hospital and community-onset infection. Infection control measures should focus not only on prevention of the spread of community strains in the hospital but also prevention of the spread of hospital strains associated with VRSA into the community.
PMCID: PMC2446903  PMID: 18508934
15.  Fungal Cell Wall Septation and Cytokinesis Are Inhibited by Bleomycins 
Antimicrobial Agents and Chemotherapy  2003;47(10):3281-3289.
When the essential and distinctive cell walls of either pathogenic or nonpathogenic fungi break, cytoplasmic membranes rupture and fungi die. This fungicidal activity was discovered previously on nonproliferating Saccharomyces cerevisiae cells treated briefly with the oxidative tool and anticancer drug family of bleomycins. The present studies investigated effects of bleomycin on growing fungal organisms. These included the medically important Aspergillus fumigatus and Cryptococcus neoformans, as well as the emerging human pathogen and fungal model, S. cerevisiae. Bleomycin had its highest potency against A. fumigatus. Scanning electron microscopy and thin-section transmission electron microscopy were used to study morphological growth characteristics. Killing and growth inhibition were also measured. Long, thin, and segmented hyphae were observed when A. fumigatus was grown without bleomycin but were never observed when the mold was grown with the drug. Bleomycin arrested conidial germination, hyphal development, and the progression and completion of cell wall septation. Similarly, the drug inhibited the construction of yeast cell wall septa, preventing cytokinesis and progression in the cell division cycle of S. cerevisiae. Even when cytoplasms of mother and daughter cells separated, septation and cell division did not necessarily occur. Bizarre cell configurations, abnormally thickened cell walls at mother-daughter necks, abnormal polarized growth, large undivided cells, fragmented cells, and empty cell ghosts were also produced. This is the first report of a fungicidal agent that arrests fungal growth and development, septum formation, and cytokinesis and that also preferentially localizes to cell walls and alters isolated cell walls as well as intact cell walls on nongrowing cells.
PMCID: PMC201140  PMID: 14506042

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